Investigation for understanding the mechanisms of tau-induced neurotoxicity by using multimodal in vivo imaging techniques

• Project/Area Number: 15K06793
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: Sahara Naruhiko 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 脳機能イメージング研究部, チームリーダー(定常) (40261185)
• Research Collaborator: Ishikawa Ai 放射線医学総合研究所, 千葉大学医学部
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: タウ / in vivo imaging / 神経毒性 / タウイメージング / 神経細胞死 / 神経炎症 / タウタンパク質毒性 / 脳老化イメージング / 脳イメージング

Outline of Final Research Achievements

Association of tau deposition with neurodegeneration in Alzheimer’s disease and related tau-positive neurological disorders indicates contribution of tau aggregates to neurotoxicity. In vivo visualization of tau accumulation would offer a reliable, objective index to aid in the diagnosis of tauopathy and to assess the disease progression. Positron emission tomography (PET) imaging of tau lesions is currently available using several tau PET ligands. Because most tau PET ligands have the property of an extrinsic fluorescent dye, these ligands are considered to be useful for both PET and fluorescence imaging. Using these advanced imaging techniques, we developed a unique diagnostic platform of in vivo imaging of tau-, neuroinflammation-PET, and volumetric MRI. Brains of living mice can be used to monitor their volume, pathological tau accumulation and neuroinflammation. Moreover, live cell imaging with two-photon microscopy allows us to capture NFT formation and neuronal death in mice.

Research Products

• [Journal Article] In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510 (2018)
  • Author(s): Ishikawa Ai、Tokunaga Masaki、Maeda Jun、Minamihisamatsu Takeharu、Shimojo Masafumi、Takuwa Hiroyuki、Ono Maiko、Ni Ruiqing、Hirano Shigeki、Kuwabara Satoshi、Ji Bin、Zhang Ming-Rong、Aoki Ichio、Suhara Tetsuya、Higuchi Makoto、Sahara Naruhiko
  • Journal Title: Journal of Alzheimer's Disease Volume: 61 Issue: 3 Pages: 1037-1052
  • DOI: 10.3233/jad-170509
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microglial activation during pathogenesis of tauopathy in rTg4510 mice: implications for the early diagnosis of tauopathy (2018)
  • Author(s): Sahara N*, Maeda J, Ishikawa I, Tokunaga M, Suhara T, Higuchi M
  • Journal Title: Journal of Alzheimer's Disease Volume: in press
  • Peer Reviewed
• [Journal Article] Comparative in-vitro quantification of pathological tau deposits and their association with neurodegeneration in tauopathy mouse models (2018)
  • Author(s): Ni R, Ji B, Ono M, Sahara N, Zhang M-R, Aoki I, Nordberg A, Suhara T, Higuchi M
  • Journal Title: J. Nuclear Medicine Volume: 117 Issue: 6 Pages: 960-966
  • DOI: 10.2967/jnumed.117.201632
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tau filaments and development of positron emission tomography (PET) tracers (2018)
  • Author(s): Goedert M*, Yamaguchi Y, Mishra S, Higuchi M, Sahara N
  • Journal Title: Frontiers in Neurology Volume: 9 Pages: 70-70
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct binding of two PET ligands, PBB3 and AV-1451, to tau fibril strains in Alzheimer’s disease and related neurodegenerative tauopathy disorders. (2017)
  • Author(s): 71.Ono M, Sahara N, Kumata K, Ji B, Ni R, Dickson DW, Trojanowski JQ, Lee VM-Y, Yoshida M, Hozumi I, Yoshiyama Y, Nordberg A, Suhara T, Zhang M-R, Higuchi M.
  • Journal Title: Brain Volume: 140 Pages: 764-780
  • DOI: 10.1093/brain/aww339
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Fluorescence and autoradiographic evaluation of tau PET ligand PBB3 to a-synuclein pathology. (2017)
  • Author(s): Koga S, Ono M, Sahara N, Higuchi M, Dickson DW.
  • Journal Title: Movement Disorder Volume: - Issue: 6 Pages: 884-892
  • DOI: 10.1002/mds.27013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Altered tau isoform ratio caused by loss of Fus and Sfpq function leads to FTLD-like phenotypes (2017)
  • Author(s): Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T, Honda D, Yokoi S, Endo K, Ikenaka K, Takagi S, Iguchi Y, Sahara N, Takashima A, Okano H, Yoshida M, Warita H, Aoki M, Watanabe H, Okado H, Katsuno H, Sobue G.
  • Journal Title: Cell Reports Volume: 18 Issue: 5 Pages: 1118-1131
  • DOI: 10.1016/j.celrep.2017.01.013
  • Peer Reviewed / Open Access
• [Journal Article] In vivo tau imaging for a diagnostic platform of tauopathy using the rTg4510 mouse line (2017)
  • Author(s): Sahara N*, Shimojo M, Ono M, Takuwa H, Febo M, Higuchi M, Suhara T
  • Journal Title: Frontiers in Neurology Volume: 8 Pages: 663-663
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] タウオリゴマーの実態とその遺伝学的因果関係 (2017)
  • Author(s): 佐原成彦
  • Journal Title: 実験医学 認知症 発症前治療のために解明すべき分子病態は何か？ Volume: 35 Pages: 90-96
  • Peer Reviewed
• [Journal Article] Distinct binding of two PET ligands, PBB3 and AV-1451, to tau fibril strains in Alzheimer’s disease and related neurodegenerative tauopathy disorders. (2017)
  • Author(s): 71.Ono M, Sahara N, Kumata K, Ji B, Ni R, Dickson DW, Trojanowski JQ, Lee VM-Y, Yoshida M, Hozumi I, Yoshiyama Y, Nordberg A, Suhara T, Zhang M-R, Higuchi M.
  • Journal Title: Brain Volume: 1403 Pages: 764-780
  • Peer Reviewed / Open Access
• [Journal Article] 認知症診断ツールとしてのPETイメージング (2017)
  • Author(s): 佐原成彦
  • Journal Title: メディカルドゥ・最新精神・神経遺伝医学研究と遺伝カウンセリング Volume: 2 Pages: 80-87
• [Journal Article] Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons (2016)
  • Author(s): Imamura, K., Sahara, N., Kanaan, N. M., Tsukita, K., Kondo, T., Kutoku, Y., Ohsawa, Y., Sunada, Y., Kawakami, K., Hotta, A., Yawata, S., Watanabe, D., Hasegawa, M., Trojanowski, J. Q., Lee, V. M.-Y., Suhara, T., Higuchi, M., and Inoue, H.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 34904-34904
  • DOI: 10.1038/srep34904
  • NAID: 120005850272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo imaging of neuroinflammation in Alzheimer's disease (2016)
  • Author(s): Makoto Higuchi, Bin Ji, Jun Maeda, Naruhiko Sahara and Tetsuya Suhara
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: unsettled Issue: 2 Pages: 139-144
  • DOI: 10.1111/cen3.12308
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Alzheimer病マウスモデルを用いた生体脳イメージング研究 (2016)
  • Author(s): 佐原成彦
  • Journal Title: BIOClinica, 脳タンパク質老化と認知症制御 Volume: 31 Pages: 33-37
• [Journal Article] In vivo imaging of neuroinflammation in Alzheimer’s disease. (2016)
  • Author(s): Higuchi H, Ji B, Maeda J, Sahara N, Suhara T.
  • Journal Title: Clinical and Experimental Neuroimmunology Volume: in press Pages: 1-1
  • Peer Reviewed
• [Journal Article] タウイメージング：PBB3 (2016)
  • Author(s): 佐原 成彦, 木村 泰之
  • Journal Title: 最新医学社・認知症：診断・バイオマーカー Volume: 3 Pages: 110-116
• [Journal Article] Imaging Multimodalities for Dissecting Alzheimer's Disease: Advanced Technologies of Positron Emission Tomography and Fluorescence Imaging. (2015)
  • Author(s): Masafumi Shimojo, Makoto Higuchi, Tetsuya Suhara, Naruhiko Sahara
  • Journal Title: Frontiers in neuroscience Volume: 9 Pages: 482-482
  • DOI: 10.3389/fnins.2015.00482
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] PET Quantification of Tau Pathology in Human Brain with 11C-PBB3 (2015)
  • Author(s): Yasuyuki Kimura, Masanori Ichise, Hiroshi Ito, Hitoshi Shimada, Yoko Ikoma, Chie Seki, Harumasa Takano, Soichiro Kitamura, Hitoshi Shinotoh, Kazunori Kawamura, Ming-Rong Zhang, Naruhiko Sahara, Tetsuya Suhara, Makoto Higuchi
  • Journal Title: Journal of nuclear medicine Volume: 56 Issue: 9 Pages: 1359-1365
  • DOI: 10.2967/jnumed.115.160127
  • Peer Reviewed
• [Journal Article] タウPETイメージングによる認知症研究の新展開 (2015)
  • Author(s): 佐原 成彦, 樋口 真人
  • Journal Title: 認知症の脳画像診断：早期検出と鑑別を目指して Volume: 9 Pages: 162-167
• [Journal Article] Tau PET (2015)
  • Author(s): 遠藤 浩信, 佐原 成彦, 島田 斉
  • Journal Title: Clinical Neuroscience Volume: 10 Pages: 1156-1158
• [Journal Article] Alzheimer病マウスモデルを用いた生体脳イメージング研究 (2015)
  • Author(s): 佐原 成彦
  • Journal Title: BIOClinica, 脳タンパク質老化と認知症制御 Volume: 31 Pages: 33-37
• [Presentation] タウオパチーマウスモデルを用いた脳タンパク質老化モデル評価系の確立 (2017)
  • Author(s): 佐原成彦
  • Organizer: 日本薬理学会
  • Place of Presentation: 長崎ブリックホール（長崎市）
  • Year and Date: 2017-03-17
  • Invited
• [Presentation] Development of novel tau PET tracers, [18F]AM-PBB3 and [18F]PM-PBB3 (2017)
  • Author(s): Ono M, Kitamura S, Shimada H, Sahara N, Takuwa H, Yoshiyama Y, Trojanowski JQ, Lee VMY, Suhara T, Jang, M-K, Tamagnan G, Marek K, Higuchi M
  • Organizer: Human Amyloid Imaging Conference Secretariat
  • Place of Presentation: 米国、マイアミ
  • Year and Date: 2017-01-11
  • Int'l Joint Research
• [Presentation] Comparative study of tau PET ligands for detecting distinct tau pathologies (2017)
  • Author(s): 佐原成彦
  • Organizer: 脳タンパク質老化と認知症制御国際タウシンポジウム
  • Invited
• [Presentation] In vivo visualization of tau pathology, neurodegeneration and neuroinflammation for developing a diagnostic platform of tauopathy (2017)
  • Author(s): 佐原成彦
  • Organizer: 脳タンパク質老化と認知症制御第2回国際シンポジウム
  • Invited
• [Presentation] タウを標的とした診断・治療薬開発の現状 (2017)
  • Author(s): 佐原成彦
  • Organizer: 第３９回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会
  • Invited
• [Presentation] Visualization of microglial response to tau-induced neurodegeneration in a model of tauopathy (2017)
  • Author(s): Naruhiko Sahara, Jun Maeda, Ai Ishikawa, Maiko Ono, Hiroyuki Takuwa, Masafumi Shimojo, Takeharu Minamihisamatsu, Masaki Tokunaga, Shoko Uchida, Izumi Matsumoto, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi
  • Organizer: Alzheimer's Association International Conference
  • Int'l Joint Research
• [Presentation] Investigating combinatory phosphorylation of tau in a propagation model of tauopathy (2017)
  • Author(s): Naruhiko Sahara, Taeko Kimura, Gen Matsumoto
  • Organizer: Neuroscience 2017
  • Int'l Joint Research
• [Presentation] in vivo multimodal imaging of tauopathy revealed a rapid turnover of pathological tau inclusions in a tauopathy mouse model (2016)
  • Author(s): Sahara N, Takuwa H, Ishikawa I, Urushihata T, Minamihisamatsu T, Tokunaga M, Shimojo M, Uchida S, Matsumoto I, Zhang M-R, Suhara T, Higuchi M
  • Organizer: Society for Neuroscience
  • Place of Presentation: 米国、サンディエゴ
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] Investigating the link between pathological tau accumulation, neuroinflammation and brain atrophy in a model of tauopathy (2016)
  • Author(s): Sahara N, Ishikawa A, Tokunaga M, Minamihisamatsu T, Ono M, Uchida S, Matsumoto I, Takuwa H, Zhang M-R, Suhara T, Higuchi T
  • Organizer: Alzheimer's Association
  • Place of Presentation: カナダ、トロント
  • Year and Date: 2016-07-24
  • Int'l Joint Research
• [Presentation] The Association Between Aβ and Tau Accumulation And Its Influence On Clinical Features In Aging And Alzheimer's Disease Spectrum Brains: [11C]PBB3 PET Study (2016)
  • Author(s): Shimada H, Suhara T, Shinoto H, Endo H, Niwa F, Kitamura S, Hirano S, Kimura Y, Yamada M, Sahara N, Zhang M-R, Kuwabara S, Higuchi M
  • Organizer: Alzheimer's Association
  • Place of Presentation: カナダ、トロント
  • Year and Date: 2016-07-23
  • Int'l Joint Research
• [Presentation] マルチモーダルイメージングによる脳タンパク質老化モデル病態評価系の確立 (2016)
  • Author(s): 佐原成彦
  • Organizer: 新学術研究領域「脳タンパク質老化と認知症制御」
  • Place of Presentation: サンルートプラザ東京（千葉県浦安市）
  • Year and Date: 2016-06-04
• [Presentation] Longitudinal in vivo imaging of tau pathology, microglial activation and neuronal loss in a mouse model of tauopathy (2015)
  • Author(s): 佐原 成彦, 石川 愛, 徳永 正希, 南久松 丈晴, 前田 純, 下條 雅文, 小野 麻衣子, 内田 翔子, 松本 いづみ, 田桑 弘之, 張 明栄, 須原 哲也, 樋口 真人
  • Organizer: Neuroscience 2015, Society for Neuroscience
  • Place of Presentation: 米国・シカゴ
  • Year and Date: 2015-10-20
  • Int'l Joint Research
• [Presentation] Utility of tau imaging probe PBB3 in human and mouse brains (2015)
  • Author(s): 佐原 成彦
  • Organizer: 脳タンパク質老化と認知症制御第1回国際シンポジウム, 新学術領域脳タンパク質老化と認知症制御
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-10
  • Invited
• [Presentation] タウオリゴマー研究の総括と今後の展望 (2015)
  • Author(s): 佐原 成彦
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森
  • Year and Date: 2015-10-04
  • Invited
• [Presentation] マウスモデルを用いた、神経障害に関与するタウ病変の生体内評価系の確立 (2015)
  • Author(s): 石川 愛, 佐原 成彦, 徳永 正希, 田桑 弘之, 島田 斉, 平野 成樹, 篠遠 仁, 桑原 聡, 須原 哲也, 樋口 真人
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森
  • Year and Date: 2015-10-02
• [Presentation] [11C]PBB3 PETによるMAPT遺伝子変異症例のタウイメージング (2015)
  • Author(s): 篠遠 仁, 佐原 成彦, 島田 斉, Wszorek, Z., 池内 健, 羽生 春夫, 石井 賢二, 樋口 真人, 須原 哲也
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森
  • Year and Date: 2015-10-02
• [Presentation] Utility of Tau Imaging Probe PBB3 on a Mouse Model of Tauopathy (2015)
  • Author(s): Naruhiko Sahara, Ai Ishikawa, Masaki Tokunaga, Takeharu Minamihisamatsu, Jun Maeda, Maiko Ono, Shoko Uchida, Izumi Matsumoto, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi
  • Organizer: Alzheimer”s Association International Conference 2015
  • Place of Presentation: 米国・ワシントンD.C.
  • Year and Date: 2015-07-22
  • Int'l Joint Research
• [Presentation] タウタンパク質にとって正常と異常の違いは何か？ (2015)
  • Author(s): 佐原 成彦
  • Organizer: 第15回日本蛋白質科学会年会, 日本蛋白質科学会
  • Place of Presentation: 徳島
  • Year and Date: 2015-06-26
  • Invited
• [Presentation] タウオパチーマウスによるタウイメージング薬剤の開発 Development of tau imaging probes using the mouse model of tauopathy (2015)
  • Author(s): 石川 愛, 佐原 成彦, 徳永 正希, 南久松 丈晴, 内田 翔子, 松本 いづみ, 島田 斉, 平野 成樹, 篠遠 仁, 桑原 聡, 須原 哲也, 樋口 真人
  • Organizer: 第56回日本神経学会学術大会, 日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20